Dendritically targeted Bdnf mRNA is essential for energy balance and response to leptin

Mutations in the Bdnf gene, which produces transcripts with either short or long 3′ untranslated regions (3′UTRs), cause human obesity; however, the precise role of BDNF in the regulation of energy balance remains unknown. Here we show the relationship between long 3′UTR Bdnf mRNA, leptin, neuronal activation and body weight. We found that long 3′UTR Bdnf mRNA was enriched in dendrites of hypothalamic neurons and that insulin and leptin could stimulate its translation in dendrites. Furthermore, mice harboring a truncated long Bdnf 3′UTR developed severe hyperphagic obesity, which was completely rescued by viral expression of long 3′UTR Bdnf mRNA in the hypothalamus. In these animals the ability of leptin to activate hypothalamic neurons and to inhibit food intake was compromised despite normal activation of leptin receptors. These results reveal a novel mechanism linking leptin action to BDNF expression during hypothalamic-mediated regulation of body weight, while also implicating dendritic protein synthesis in this process.